Lee In Kyu, Song Hyerin, Kim Hyerim, Kim Ik Soo, Tran Na Ly, Kim Sang-Heon, Oh Seung Ja, Lee Ji Min
Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Korea.
Department of Molecular Bioscience, College of Biomedical Sciences, Kangwon National University, Chuncheon 24341, Korea.
Cancers (Basel). 2020 Jun 29;12(7):1733. doi: 10.3390/cancers12071733.
Retinoic acid-related orphan receptor α (RORα) functions as a transcription factor for various biological processes, including circadian rhythm, inflammation, cancer, and lipid metabolism. Here, we demonstrate that RORα is crucial for maintaining cholesterol homeostasis in CD8 T cells by attenuating NF-kB transcriptional activity. Cholesterol sulfate, the established natural agonist of RORα, exhibits cellular cytotoxicity on, and increased effector responses in, CD8 T cells. Transcript analysis reveals that the suppression of RORα leads to the upregulation of NF-kB target genes in T cells. Chromatin immunoprecipitation analysis was used to determine the corecruitment of RORα and histone deacetylase (HDAC) on NF-kB target promoters and the subsequent dismissal of coactivators for transcriptional repression. We demonstrate that RORα/HDAC-mediated attenuation of NF-kB signaling controls the balance of cholesterol metabolism in CD8 T cells, and that therapeutic strategies targeting this epigenetic regulation could be beneficial to the treatment of solid tumors including colon cancers.
维甲酸相关孤儿受体α（RORα）作为一种转录因子参与多种生物学过程，包括昼夜节律、炎症、癌症和脂质代谢。在此，我们证明RORα通过减弱NF-κB转录活性对维持CD8 T细胞中的胆固醇稳态至关重要。硫酸胆固醇是已确定的RORα天然激动剂，对CD8 T细胞具有细胞毒性并增强效应反应。转录分析表明，RORα的抑制导致T细胞中NF-κB靶基因的上调。染色质免疫沉淀分析用于确定RORα和组蛋白去乙酰化酶（HDAC）在NF-κB靶启动子上的共募集以及随后共激活因子的解离以进行转录抑制。我们证明RORα/HDAC介导的NF-κB信号减弱控制了CD8 T细胞中胆固醇代谢的平衡，并且针对这种表观遗传调控的治疗策略可能有益于包括结肠癌在内的实体瘤的治疗。
